In patients with chronic heart failure (CHF) difficulty to breathe, and premature fatigue are the main symptoms limiting the patient's exercise tolerance, and ability to perform activities of daily life. During his clinical training the candidate treated several patients with CHF complaining of shortness of breath and fatigue. The candidate has a clinical background in physical therapy, and has been undergoing training (Ph.D. and postdoctoral) in the field of physiology to understand muscle weakness and fatigue. During this process the candidate has published 24 studies in peer-reviewed journals (13 first-author). The candidate's short-term goal is two-fold: to investigate the cellular and molecular mechanisms of respiratory muscle weakness and fatigue in heart failure;and ii) become an independent scientist. In the long-term the candidate's career goal is to become a tenured Professor heading a laboratory performing studies to understand mechanisms, and develop novel therapies to exercise intolerance experienced by patients with chronic cardiopulmonary diseases. As an independent investigator the candidate will have the rare expertise of applying discoveries at the cellular and molecular level to whole-body physiology, and bridge the gap between basic and clinical sciences. The research career development plan was designed to enhance the candidate's research skills and promote independence. The career development plan includes coursework in muscle physiology (relevant to respiratory muscle), molecular biology and cell signaling, and responsible conduct of research and ethics. These courses will complement the candidates training in clinical science, and whole-body/integrative physiology. Three senior scientists will mentor the candidate during the training component. These individuals have expertise in primary areas studied in the research plan (skeletal muscle physiology, sphingolipid biology, and respiratory failure and translational science). In addition to interacting with each mentor individually, the candidate and all mentors will meet to discuss research findings, plan future directions, and evaluate progress. The mentors will also assist directly in the transition to independence by performing mock faculty-search interviews, and discussing negotiation strategies. The project performance site is the University of Kentucky (U.K.). The Center for Muscle Biology and Gill Heart Institute are part of U.K. and key to the success of the candidate's training. The laboratory of mentors and collaborators can provide the support necessary to complete the mentored phase of this award. Most individuals involved in the project are faculty in the candidate's and primary mentor's department (Dept. of Physiology). All mentors and collaborators are leaders in their field of research, and have trained graduate students and post-docs. Courses proposed are offered as part of the U.K. Integrated Biomedical Sciences Graduate Program, and the candidate has been admitted to the U.K. Graduate School and will readily enroll for courses when this award is made. Respiratory muscle weakness contributes to the morbidity and mortality of patients with CHF. Published reports show that increased plasma sphingomyelinase (SMase) activity is associated with muscle weakness in CHF patients. Our preliminary data suggest that SMase mimics the effect of CHF on the diaphragm (i.e., oxidative stress and weakness). It appears that SMase mediates diaphragm weakness through activation of NAD(P)H oxidase that leads to oxidative stress. Oxidative stress impairs calcium regulation and the function of the contractile apparatus. The research plan was designed to elucidate the mechanisms of respiratory muscle weakness and fatigue in CHF. To accomplish this goal we will address three specific aims: Aim 1. To identify intramyocyte mechanisms mediating diaphragm muscle dysfunction in CHF. Aim 2. To define SMase as a mediator of diaphragm muscle dysfunction in CHF. Aim 3: To test the role of NAD(P)H oxidase on diaphragm muscle dysfunction of CHF mice. PUBLIC HEALTH RELEVANCE: NARRATIVE Patients with heart failure due to, for example, heart attack or long history of high blood pressure have weakness of the respiratory muscles that contribute to shortness of breath. The goal of this project is to identify the key mechanisms that cause respiratory muscle dysfunction in heart failure. This will facilitate the development of new therapies to prevent weakness and fatigue of the respiratory muscles in patients with heart failure. Improvement of the respiratory muscle function should increase the patient's ability to perform daily tasks, and enhance quality of life.